CA1256105A - Substituted 1,8-naphthyridinones, processes for their preparation and pharmaceutical compositions containing them - Google Patents
Substituted 1,8-naphthyridinones, processes for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- CA1256105A CA1256105A CA000504729A CA504729A CA1256105A CA 1256105 A CA1256105 A CA 1256105A CA 000504729 A CA000504729 A CA 000504729A CA 504729 A CA504729 A CA 504729A CA 1256105 A CA1256105 A CA 1256105A
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- compound
- naphthyridin
- carbon atoms
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 29
- 238000002360 preparation method Methods 0.000 title claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- ZFRUGZMCGCYBRC-UHFFFAOYSA-N 1h-1,8-naphthyridin-2-one Chemical class C1=CC=NC2=NC(O)=CC=C21 ZFRUGZMCGCYBRC-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 80
- 239000001257 hydrogen Substances 0.000 claims abstract description 80
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 49
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 26
- -1 pyrrolidino, piperidino, morpholino Chemical group 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 125000002346 iodo group Chemical group I* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- JUZJTPUHNNXUFV-UHFFFAOYSA-N 2-(bromomethyl)-9-phenyl-2,3-dihydrofuro[2,3-b][1,8]naphthyridin-4-one Chemical compound O1C(CBr)CC(C(C2=CC=CN=C22)=O)=C1N2C1=CC=CC=C1 JUZJTPUHNNXUFV-UHFFFAOYSA-N 0.000 claims description 5
- QQEGBDXWCXNFFJ-UHFFFAOYSA-N 2-(iodomethyl)-9-phenyl-2,3-dihydrofuro[2,3-b][1,8]naphthyridin-4-one Chemical compound O1C(CI)CC(C(C2=CC=CN=C22)=O)=C1N2C1=CC=CC=C1 QQEGBDXWCXNFFJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- NSJBYBKVUQNONP-UHFFFAOYSA-N 2-(bromomethyl)-9-(3-methoxyphenyl)-2,3-dihydrofuro[2,3-b][1,8]naphthyridin-4-one Chemical compound COC1=CC=CC(N2C3=NC=CC=C3C(=O)C=3CC(CBr)OC=32)=C1 NSJBYBKVUQNONP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- HBWBTJKIVBGJLC-UHFFFAOYSA-N (4-oxo-5-phenyl-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-2-yl)methyl acetate Chemical compound O1C(COC(=O)C)CC(C2=O)=C1C1=CC=CN=C1N2C1=CC=CC=C1 HBWBTJKIVBGJLC-UHFFFAOYSA-N 0.000 claims description 2
- LALOUMSMGLUTAO-UHFFFAOYSA-N 2-(bromomethyl)-9-(3-chlorophenyl)-2,3-dihydrofuro[2,3-b][1,8]naphthyridin-4-one Chemical compound ClC1=CC=CC(N2C3=NC=CC=C3C(=O)C=3CC(CBr)OC=32)=C1 LALOUMSMGLUTAO-UHFFFAOYSA-N 0.000 claims description 2
- OELDTIWXMHIDIT-UHFFFAOYSA-N 2-(iodomethyl)-5-(3-methoxyphenyl)-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-4-one Chemical compound COC1=CC=CC(N2C(C=3CC(CI)OC=3C3=CC=CN=C32)=O)=C1 OELDTIWXMHIDIT-UHFFFAOYSA-N 0.000 claims description 2
- JXBDBSILRPHFGO-UHFFFAOYSA-N 2-methylidene-9-phenyl-3h-furo[2,3-b][1,8]naphthyridin-4-one Chemical compound O1C(=C)CC(C(C2=CC=CN=C22)=O)=C1N2C1=CC=CC=C1 JXBDBSILRPHFGO-UHFFFAOYSA-N 0.000 claims description 2
- QCHCJCGXQGQVCC-UHFFFAOYSA-N 5-(3-chlorophenyl)-2-(hydroxymethyl)-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-4-one Chemical compound O1C(CO)CC(C2=O)=C1C1=CC=CN=C1N2C1=CC=CC(Cl)=C1 QCHCJCGXQGQVCC-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- BDKGFYQKHSCUKL-UHFFFAOYSA-N 9-phenyl-2-(pyrrolidin-1-ylmethyl)-2,3-dihydrofuro[2,3-b][1,8]naphthyridin-4-one Chemical compound O1C=2N(C=3C=CC=CC=3)C3=NC=CC=C3C(=O)C=2CC1CN1CCCC1 BDKGFYQKHSCUKL-UHFFFAOYSA-N 0.000 claims description 2
- YHZDSQYKPVAQAT-UHFFFAOYSA-N [5-(3-methoxyphenyl)-4-oxo-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-2-yl]methyl acetate Chemical compound COC1=CC=CC(N2C(C=3CC(COC(C)=O)OC=3C3=CC=CN=C32)=O)=C1 YHZDSQYKPVAQAT-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 5
- UPJYKJSBKXUULC-UHFFFAOYSA-N (5-oxo-6-phenyl-3,4-dihydro-2h-pyrano[3,2-c][1,8]naphthyridin-3-yl) acetate Chemical compound C1C(OC(=O)C)COC(C2=CC=CN=C22)=C1C(=O)N2C1=CC=CC=C1 UPJYKJSBKXUULC-UHFFFAOYSA-N 0.000 claims 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- RNHNDGRYLBOFBW-UHFFFAOYSA-N 2-(hydroxymethyl)-5-(3-methoxyphenyl)-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-4-one Chemical compound COC1=CC=CC(N2C(C=3CC(CO)OC=3C3=CC=CN=C32)=O)=C1 RNHNDGRYLBOFBW-UHFFFAOYSA-N 0.000 claims 1
- OAIOMDDNQQKMQA-UHFFFAOYSA-N 2-(hydroxymethyl)-5-phenyl-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-4-one Chemical compound O1C(CO)CC(C2=O)=C1C1=CC=CN=C1N2C1=CC=CC=C1 OAIOMDDNQQKMQA-UHFFFAOYSA-N 0.000 claims 1
- VMQNSNGLTHWXBF-UHFFFAOYSA-N 2-(iodomethyl)-5-phenyl-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-4-one Chemical compound O1C(CI)CC(C2=O)=C1C1=CC=CN=C1N2C1=CC=CC=C1 VMQNSNGLTHWXBF-UHFFFAOYSA-N 0.000 claims 1
- IOJNBFJNPZMVMH-UHFFFAOYSA-N 3-hydroxy-6-phenyl-3,4-dihydro-2h-pyrano[3,2-c][1,8]naphthyridin-5-one Chemical compound C1C(O)COC(C2=CC=CN=C22)=C1C(=O)N2C1=CC=CC=C1 IOJNBFJNPZMVMH-UHFFFAOYSA-N 0.000 claims 1
- ITWAFVDKENFKGD-UHFFFAOYSA-N 5-phenyl-2-(pyrrolidin-1-ylmethyl)-2,3-dihydrofuro[3,2-c][1,8]naphthyridin-4-one Chemical compound O1C=2C3=CC=CN=C3N(C=3C=CC=CC=3)C(=O)C=2CC1CN1CCCC1 ITWAFVDKENFKGD-UHFFFAOYSA-N 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 230000003266 anti-allergic effect Effects 0.000 abstract description 3
- 230000001120 cytoprotective effect Effects 0.000 abstract description 2
- 125000001589 carboacyl group Chemical group 0.000 abstract 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000243 solution Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- 239000007788 liquid Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 229920000609 methyl cellulose Polymers 0.000 description 7
- 239000001923 methylcellulose Substances 0.000 description 7
- 235000010981 methylcellulose Nutrition 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- DHSUHPJUEBYIIS-UHFFFAOYSA-N 4-hydroxy-1-phenyl-3-prop-2-enyl-1,8-naphthyridin-2-one Chemical compound C12=NC=CC=C2C(O)=C(CC=C)C(=O)N1C1=CC=CC=C1 DHSUHPJUEBYIIS-UHFFFAOYSA-N 0.000 description 5
- 206010006482 Bronchospasm Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 229940098773 bovine serum albumin Drugs 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 208000009079 Bronchial Spasm Diseases 0.000 description 3
- 208000014181 Bronchial disease Diseases 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000002052 anaphylactic effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LKJRSIKJPNFWNO-UHFFFAOYSA-N (2-oxo-1-phenyl-3-prop-2-enyl-1,8-naphthyridin-4-yl) acetate Chemical compound C12=NC=CC=C2C(OC(=O)C)=C(CC=C)C(=O)N1C1=CC=CC=C1 LKJRSIKJPNFWNO-UHFFFAOYSA-N 0.000 description 2
- WKYRBKKTPWIHNV-UHFFFAOYSA-N 1-phenyl-4-prop-2-enoxy-1,8-naphthyridin-2-one Chemical compound C12=NC=CC=C2C(OCC=C)=CC(=O)N1C1=CC=CC=C1 WKYRBKKTPWIHNV-UHFFFAOYSA-N 0.000 description 2
- 208000000104 Arthus reaction Diseases 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 230000007885 bronchoconstriction Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- GDPGTZHBZCLNJY-UHFFFAOYSA-N 2-(bromomethyl)-9-phenyl-2,3-dihydrofuro[2,3-b][1,8]naphthyridin-4-one;hydrobromide Chemical compound Br.O1C(CBr)CC(C(C2=CC=CN=C22)=O)=C1N2C1=CC=CC=C1 GDPGTZHBZCLNJY-UHFFFAOYSA-N 0.000 description 1
- QXPJNXVVWFMBFK-UHFFFAOYSA-N 3-but-3-enyl-4-hydroxy-1-phenyl-1,8-naphthyridin-2-one Chemical compound C12=NC=CC=C2C(O)=C(CCC=C)C(=O)N1C1=CC=CC=C1 QXPJNXVVWFMBFK-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
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- IWGDPBQTRGLPHM-UHFFFAOYSA-N 4-hydroxy-1-phenyl-1,8-naphthyridin-2-one Chemical compound C12=NC=CC=C2C(O)=CC(=O)N1C1=CC=CC=C1 IWGDPBQTRGLPHM-UHFFFAOYSA-N 0.000 description 1
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- 241000700198 Cavia Species 0.000 description 1
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- 241000609499 Palicourea Species 0.000 description 1
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- 229920001615 Tragacanth Polymers 0.000 description 1
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- 150000008065 acid anhydrides Chemical class 0.000 description 1
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- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
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- 238000009395 breeding Methods 0.000 description 1
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- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- XTQQEFBWUFUXSZ-UHFFFAOYSA-N methyl 2-anilinopyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1NC1=CC=CC=C1 XTQQEFBWUFUXSZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 210000005164 penile vein Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
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- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 238000012795 verification Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
ABSTRACT
Substituted 1,8-naphthyridinones of formulae V, VI or VII
VI
V VII
wherein n is 1 or 2; R1 and R2 may be combined to form a bond, or R1 is hydrogen and R2 is OR, halogen or NR3R4; R
is hydrogen, carboxylic acyl or carbamyl; R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring; R5 is hydrogen or carboxylic acyl; and Y is CH or N.
The compounds possess anti-allergic, anti-inflammatory and cytoprotective activity.
Substituted 1,8-naphthyridinones of formulae V, VI or VII
VI
V VII
wherein n is 1 or 2; R1 and R2 may be combined to form a bond, or R1 is hydrogen and R2 is OR, halogen or NR3R4; R
is hydrogen, carboxylic acyl or carbamyl; R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring; R5 is hydrogen or carboxylic acyl; and Y is CH or N.
The compounds possess anti-allergic, anti-inflammatory and cytoprotective activity.
Description
~2~6~0S
SUBSTITUTED 1,8-NAPHTHYRIDINONES, PROCESSES FOR
THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM
The present invention relates to novel tricyclic compounds which possess anti-allergic, anti-inflammatory, and cytoprotective activity.
The compounds of the present invention are compounds of the formula ~ N ~ J
~(~P
wherein A is a moiety of the formula II, III or IV
iLZ56~0S
O~CH2R2 J~(cH2)n ~ORS
(CH2)n ~1~ O~ R1 /~
O CH2R2 o II III IV
wherein n is 1 or 2;
Rl and R2 may be combined to form a bond, or is hydrogen and R2 is OR, halogen or NR3R4;
R is hydrogen, R6-CtO)-7 or R7R8NC(o)-;
R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring;
R5 is hydrogen or R6-CtO)-;
R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms;
X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2;
;
256~05 p is 1, 2 or 3; and Y is CH or N:
and the acid addition salts thereof.
The compounds of formula I can also be represented by formulae V, VI and VII
0~ CH2R2 y O~oR5 N~o~C l R~
VI
V VII
wherein Rl, R2, R5, X, Y, n and p are as defined above.
Compounds of formulae V and VI wherein Rl is hydrogen have at least one asymmetric carbon atom, i.e., the carbon indicated with an asterisk(*) in formulae V
and VI. The compounds accordin~ly exist in enantiomeric forms or in racemic mixtures thereof, and all such isomers and racemic mixtures are within the scope of this invention. Separation of the isomers may be accomplished by methods well known to those skilled in the art.
The compounds of formulae V, VI and VII can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
~5~
., As used herein, the term "alkyl" refers to straight or branched chain groups, e.g. methyl, ethyl,-propyl, isopropyl, butyl, isobutyl and hexyl. Examples of "alkoxy" groups are methoxy, ethoxy, isopropoxy, butoxy and hexoxy. "Halogen" refers to fluorine, chlorine, bromine and iodine.
The term "acid addition salts" as used herein refers to salts formed with pharmaceutically acceptable acids such as, for example, hydrochloric, hydrobromic, methane sulfonic and sulfuric acids.
Preferred are compounds of formulae V and VI, with compounds o~ formula V being more preferred.
Preferred compounds of formulae V and VI are those wherein n is 1~
A third group of preferred compounds is that wherein Y is CH.
A fourth group of preferred compounds is that wherein Rl is hydrogen and R2 is OR wherein R is hydrogen or R6C(O)-, preferably R being hydrogen or R6C(O)-, wherein R6 is alkyl.
A further group of preferred compounds is that wherein Rl is hydrogen and R2 is NR3R4, preferably being l-piperidinyl or l-pyrrolidinyl.
A further group of preferred compounds is that wherein Rl is hydrogen and R2 is halogen, preferably bromo or iodo.
Still another group of preferred compounds is that wherein p is 1 and X is hydrogen, halogen or alkoxy, preferably hydrogen, chloro or methoxy, preferably the substituent being in meta-position.
Also contemplated as part of this invention are pharmaceutical compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.
The compounds of this invention are useful for treatinq allergic reactions and inflammation.
It is also contemplated that compounds of the invention are useful in the treatment of peptic ulcers.
The compounds of this invention can be prepared according to known methods. In the followinq equations suitable methods are described. Reactive groups not involved in the described reaction are protected according to standard methods before the reaction and are subsequently deprotected to yield the desired product.
The starting compounds used in the described processes can be prepared according to known methods.
In the formulae of the following description of the processes, unless stated otherwise, n is 1 or 2;
Rl and R2 may be combined to form a bond, or is hydroqen and R2 is OR, haloqen or NR3R4;
R is hydroqen, R6-C(O)-, or R7R3NC(o)-;
R3 and R4 are inde~endently hydro~en or alkyl havinq from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino rinq:
R5 is hydroqen or R6-C(O)-;
R6 is alkyl havinq from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl havin~ from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms;
` ~2S6~(~S
X i8 hydrogen, hydroxy, alkyl havin~ from I to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2:
p is 1, 2 or 3: and Y is CH or N:
including suitable protecting groups.
The processes are particularly useful for the preparation of compounds of formulae V and VI wherein Y
is CH and n is 1 and of formula VII wherein Y is CH.
(a) For the preparation of compounds of formulae V and VI wherein Rl is hydrogen and R2 is halogen, a compound of formula VIII
OH
~ YX~X (CH2)n-CH=CH2 p VIII
or an ester thereof is subjected to halogenation and cyclisation. This procedure is particularly useful for the preparation of compounds wherein Y is CH and n is 1.
For example, for the preparation of compounds of formulae V and VI wherein ~1 is hydrogen and R2 is bromo, a compound VIII or its 4-ester is subjected to bromination, which results in spontaneous cyclization of ~25610~i the intermediate dibromo compound. The bromination can be carried out at reduced temperatures (-10 to +32C), by adding bromine to the solution of the compound VIII and letting the reaction mixture come to room temperature.
Preferably equimolar amounts of compound vIrI and bromine are used. After the isolation of the reaction product compounds V and vI are isolated, for example, by column chromatography.
For the preparation of compounds of formulas V
and VI wherein Rl is hydro~en and R2 is iodo, a compound of formula VIII or its 4-ester is reacted with N-iodo-quccinimide in the presence of perchloric acid at reduced temperature. The compounds V and VI are isolated by e.g., column chromatography.
A variant of the process for preparing compounds of formula VI wherein Rl-is hydrogen and R2 is iodo comprises reacting a compound of formula VIII with iodine monochloride in a halogenated hydrocarbon as solvent such as, for example, methylene chloride, perferably at room temperature. Equimolar amounts of the compound VIII and iodine monochloride, or preferably, a small excess of iodine monochloride is used.
A further variant of the process for preparin~
compounds of formula VI wherein Rl is hydrogen and R2 is iodo comprises reacting a compound of formula VIII with an equimolar amount (or small excess) of iodine in a halogenated hydrocarbon as solvent (e.g., methylene chloride) in an alkaline medium.
b) A compound of formula IX
~~"` ~256105 -a-OH,0~
(CH2)n~ CH - CH2 p IX
or ester thereof is cyclized to form a compound of formula V wherein Rl is hydrogen and R2 is hydroxy.
The cyclization can be carried out by heating, if desired, a solution of compound of formula IX. The compound IX can be obtained by reacting the corresponding compound of formula VIII with peracetic acid in a solvent (e.g., ethylacetate or a halogenated hydrocarbon, e.q., methylene chloride) at 20 to 3~C, ~referably around room temperature. Without isolating the compound IX the desired end product V can be obtained.
c) Compounds of formulae V, VI and VII, wherein Rl is hydrogen, R2 is hydroxy and RS is hydrogen can be prepared by hydrolysis of a compound of formula V
or VI, wherein Rl is hydrogen and R2 is halogen.
A compound of formula VI wherein Rl is hydrogen and R2 is halogen, preferably bromo, can be subjected to hydrolysis by refluxing the reaction mixture containing water, sodium hydroxide and, possibly, methanol, yielding, besides possible side products, a compound of formula V wherein Rl is hydrogen, and R2 is hydroxy and (when n is one) of formula VII wherein R5 is hydrogen.
The compounds are isolated by techniques known in the art. If the compound of formula VI wherein Rl is hydrogen and R2 is halogen (preferably bromo) is subjected to hydrolysis under very mild conditions te.q.
g silver acetate in aqueous methanol at room temperature), the corresponding compound of formula VI is obtained wherein Rl is hydro~en and R2 is hydroxy.
d) A compound of formula V or VI wherein Rl is hydrogen and R2 is hydroxy or VII wherein R5 is hydrogen can be esterfied to form the corresponding respective com~ound of formula V, VI or VII. Therein Rl is hydrogen, R2 is OR, wherein R is R6C(O)- or R7R8NC(o)-and R5 is R6C(O)-, wherein R6 is alkyl having from 1 to 9 carbon atoms, alkenyl havinq from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, ~henyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl and R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon ato~s, or hydroxyalkyl having from 1 to 6 carbon atoms. This process is carried out usinq acylating processes known in the art, such as reacting the hydroxy compound with the appropriate acid anhydride or acyl chloride in an inert solvent such as, ~or example, benzene.
e) A compound of formula V or VI wherein Rl is hydrogen and R is haloqen, preferably bromo, is reacted with an amine HNR3R4 (wherein Q3 and R4 are independentl~
hydro en or alkyl havin~ from 1 to 6 carbon atoms, or R3 and R may be combined with the nitronen to which they are attached to form a pyrrolidino, oiperidino, morpholino or piperazino ring) or with a reactive derivative of said amine to form the respective corresponding compound V or VI wherein Rl is hydrogen and R2 is NR3R4. The reaction can be carried out at room temperature.
~; f) A compound of formula V or VI wherein Rl is hydrogen and R2 is halogen, preferably iodo, is dehydro-` ~256~05 halogenated to form the respective correspondinq compound v or VI wherein Rl and R2 tog~ther form a bond. The reaction can be carried out at room temperature in the presence of a base, preferably an organic base such as, for example, piperidine.
g) A compound of formula VI wherein Rl is hydrogen and R2 is bromo can be reacted with sodium iodide to yield a compound of formula V wherein Rl is hydrogen and R2 is iodo. The reaction can be carried out in a solvent such as, for example, acetone.
h) A compound of formula V, VI or VII, wherein Rl is hydroqen, R2 is OR, wherein R is R6-C(O)-, or R7R8NC(o)-;
RS is hydrogen or R6-C(O)-;
R6 is alkyl havinq from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms, can be hydrolyzed to yield the respective corresponding compound of formula V, VI or VII wherein Rl is hydrogen, R2 is hydroxy and R5 is hydrogen. The hydrolysis can be carried out in an aqueous alkaline medium, if desired also containing an alcohol (e.g., methanol). Preferably the hydrolysis is carried out with NaOH (preferably 0.5 NaOH) under reflux of the aqueous alcohol-free medium.
(i) A compound of formula V or VI wherein Rl is hydrogen and R2 is hydroxy is dehydrated to form the corresponding respective compound of formula V or VI
~256~05 wherein Rl and R2 together form a bond. The reaction can be carried out with dicyclohexylcarbodiimide (DCC) in the presence of a catalyst such as, for example, CuCl in an organic solvent such as an ether, preferably diethylether.
The above processes are followed by isolation of the individual compounds and/or formation of salts and/or solvates. The compounds in their enantiomeric form can be isolated from the racemic mixture according to known methods.
Compounds of formula VIII may be prepared by methods known in the art. See, for example, U.S. Patent 4,492,702. An example of such a procedure is provided in Preparation 1.
Representative of the compounds of this invention of formulae V, VI and VII are the following:
3,5-dihydro-2-(hydroxymethyl)-5-phenyl-furo(3,2-c)-1,8-naphthyridin-4~2H)-one, 5-(3-chlorophenyl)-3,5-dihydro-2-(hydroxymethyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one,
SUBSTITUTED 1,8-NAPHTHYRIDINONES, PROCESSES FOR
THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM
The present invention relates to novel tricyclic compounds which possess anti-allergic, anti-inflammatory, and cytoprotective activity.
The compounds of the present invention are compounds of the formula ~ N ~ J
~(~P
wherein A is a moiety of the formula II, III or IV
iLZ56~0S
O~CH2R2 J~(cH2)n ~ORS
(CH2)n ~1~ O~ R1 /~
O CH2R2 o II III IV
wherein n is 1 or 2;
Rl and R2 may be combined to form a bond, or is hydrogen and R2 is OR, halogen or NR3R4;
R is hydrogen, R6-CtO)-7 or R7R8NC(o)-;
R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring;
R5 is hydrogen or R6-CtO)-;
R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms;
X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2;
;
256~05 p is 1, 2 or 3; and Y is CH or N:
and the acid addition salts thereof.
The compounds of formula I can also be represented by formulae V, VI and VII
0~ CH2R2 y O~oR5 N~o~C l R~
VI
V VII
wherein Rl, R2, R5, X, Y, n and p are as defined above.
Compounds of formulae V and VI wherein Rl is hydrogen have at least one asymmetric carbon atom, i.e., the carbon indicated with an asterisk(*) in formulae V
and VI. The compounds accordin~ly exist in enantiomeric forms or in racemic mixtures thereof, and all such isomers and racemic mixtures are within the scope of this invention. Separation of the isomers may be accomplished by methods well known to those skilled in the art.
The compounds of formulae V, VI and VII can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
~5~
., As used herein, the term "alkyl" refers to straight or branched chain groups, e.g. methyl, ethyl,-propyl, isopropyl, butyl, isobutyl and hexyl. Examples of "alkoxy" groups are methoxy, ethoxy, isopropoxy, butoxy and hexoxy. "Halogen" refers to fluorine, chlorine, bromine and iodine.
The term "acid addition salts" as used herein refers to salts formed with pharmaceutically acceptable acids such as, for example, hydrochloric, hydrobromic, methane sulfonic and sulfuric acids.
Preferred are compounds of formulae V and VI, with compounds o~ formula V being more preferred.
Preferred compounds of formulae V and VI are those wherein n is 1~
A third group of preferred compounds is that wherein Y is CH.
A fourth group of preferred compounds is that wherein Rl is hydrogen and R2 is OR wherein R is hydrogen or R6C(O)-, preferably R being hydrogen or R6C(O)-, wherein R6 is alkyl.
A further group of preferred compounds is that wherein Rl is hydrogen and R2 is NR3R4, preferably being l-piperidinyl or l-pyrrolidinyl.
A further group of preferred compounds is that wherein Rl is hydrogen and R2 is halogen, preferably bromo or iodo.
Still another group of preferred compounds is that wherein p is 1 and X is hydrogen, halogen or alkoxy, preferably hydrogen, chloro or methoxy, preferably the substituent being in meta-position.
Also contemplated as part of this invention are pharmaceutical compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.
The compounds of this invention are useful for treatinq allergic reactions and inflammation.
It is also contemplated that compounds of the invention are useful in the treatment of peptic ulcers.
The compounds of this invention can be prepared according to known methods. In the followinq equations suitable methods are described. Reactive groups not involved in the described reaction are protected according to standard methods before the reaction and are subsequently deprotected to yield the desired product.
The starting compounds used in the described processes can be prepared according to known methods.
In the formulae of the following description of the processes, unless stated otherwise, n is 1 or 2;
Rl and R2 may be combined to form a bond, or is hydroqen and R2 is OR, haloqen or NR3R4;
R is hydroqen, R6-C(O)-, or R7R3NC(o)-;
R3 and R4 are inde~endently hydro~en or alkyl havinq from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino rinq:
R5 is hydroqen or R6-C(O)-;
R6 is alkyl havinq from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl havin~ from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms;
` ~2S6~(~S
X i8 hydrogen, hydroxy, alkyl havin~ from I to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2:
p is 1, 2 or 3: and Y is CH or N:
including suitable protecting groups.
The processes are particularly useful for the preparation of compounds of formulae V and VI wherein Y
is CH and n is 1 and of formula VII wherein Y is CH.
(a) For the preparation of compounds of formulae V and VI wherein Rl is hydrogen and R2 is halogen, a compound of formula VIII
OH
~ YX~X (CH2)n-CH=CH2 p VIII
or an ester thereof is subjected to halogenation and cyclisation. This procedure is particularly useful for the preparation of compounds wherein Y is CH and n is 1.
For example, for the preparation of compounds of formulae V and VI wherein ~1 is hydrogen and R2 is bromo, a compound VIII or its 4-ester is subjected to bromination, which results in spontaneous cyclization of ~25610~i the intermediate dibromo compound. The bromination can be carried out at reduced temperatures (-10 to +32C), by adding bromine to the solution of the compound VIII and letting the reaction mixture come to room temperature.
Preferably equimolar amounts of compound vIrI and bromine are used. After the isolation of the reaction product compounds V and vI are isolated, for example, by column chromatography.
For the preparation of compounds of formulas V
and VI wherein Rl is hydro~en and R2 is iodo, a compound of formula VIII or its 4-ester is reacted with N-iodo-quccinimide in the presence of perchloric acid at reduced temperature. The compounds V and VI are isolated by e.g., column chromatography.
A variant of the process for preparing compounds of formula VI wherein Rl-is hydrogen and R2 is iodo comprises reacting a compound of formula VIII with iodine monochloride in a halogenated hydrocarbon as solvent such as, for example, methylene chloride, perferably at room temperature. Equimolar amounts of the compound VIII and iodine monochloride, or preferably, a small excess of iodine monochloride is used.
A further variant of the process for preparin~
compounds of formula VI wherein Rl is hydrogen and R2 is iodo comprises reacting a compound of formula VIII with an equimolar amount (or small excess) of iodine in a halogenated hydrocarbon as solvent (e.g., methylene chloride) in an alkaline medium.
b) A compound of formula IX
~~"` ~256105 -a-OH,0~
(CH2)n~ CH - CH2 p IX
or ester thereof is cyclized to form a compound of formula V wherein Rl is hydrogen and R2 is hydroxy.
The cyclization can be carried out by heating, if desired, a solution of compound of formula IX. The compound IX can be obtained by reacting the corresponding compound of formula VIII with peracetic acid in a solvent (e.g., ethylacetate or a halogenated hydrocarbon, e.q., methylene chloride) at 20 to 3~C, ~referably around room temperature. Without isolating the compound IX the desired end product V can be obtained.
c) Compounds of formulae V, VI and VII, wherein Rl is hydrogen, R2 is hydroxy and RS is hydrogen can be prepared by hydrolysis of a compound of formula V
or VI, wherein Rl is hydrogen and R2 is halogen.
A compound of formula VI wherein Rl is hydrogen and R2 is halogen, preferably bromo, can be subjected to hydrolysis by refluxing the reaction mixture containing water, sodium hydroxide and, possibly, methanol, yielding, besides possible side products, a compound of formula V wherein Rl is hydrogen, and R2 is hydroxy and (when n is one) of formula VII wherein R5 is hydrogen.
The compounds are isolated by techniques known in the art. If the compound of formula VI wherein Rl is hydrogen and R2 is halogen (preferably bromo) is subjected to hydrolysis under very mild conditions te.q.
g silver acetate in aqueous methanol at room temperature), the corresponding compound of formula VI is obtained wherein Rl is hydro~en and R2 is hydroxy.
d) A compound of formula V or VI wherein Rl is hydrogen and R2 is hydroxy or VII wherein R5 is hydrogen can be esterfied to form the corresponding respective com~ound of formula V, VI or VII. Therein Rl is hydrogen, R2 is OR, wherein R is R6C(O)- or R7R8NC(o)-and R5 is R6C(O)-, wherein R6 is alkyl having from 1 to 9 carbon atoms, alkenyl havinq from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, ~henyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl and R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon ato~s, or hydroxyalkyl having from 1 to 6 carbon atoms. This process is carried out usinq acylating processes known in the art, such as reacting the hydroxy compound with the appropriate acid anhydride or acyl chloride in an inert solvent such as, ~or example, benzene.
e) A compound of formula V or VI wherein Rl is hydrogen and R is haloqen, preferably bromo, is reacted with an amine HNR3R4 (wherein Q3 and R4 are independentl~
hydro en or alkyl havin~ from 1 to 6 carbon atoms, or R3 and R may be combined with the nitronen to which they are attached to form a pyrrolidino, oiperidino, morpholino or piperazino ring) or with a reactive derivative of said amine to form the respective corresponding compound V or VI wherein Rl is hydrogen and R2 is NR3R4. The reaction can be carried out at room temperature.
~; f) A compound of formula V or VI wherein Rl is hydrogen and R2 is halogen, preferably iodo, is dehydro-` ~256~05 halogenated to form the respective correspondinq compound v or VI wherein Rl and R2 tog~ther form a bond. The reaction can be carried out at room temperature in the presence of a base, preferably an organic base such as, for example, piperidine.
g) A compound of formula VI wherein Rl is hydrogen and R2 is bromo can be reacted with sodium iodide to yield a compound of formula V wherein Rl is hydrogen and R2 is iodo. The reaction can be carried out in a solvent such as, for example, acetone.
h) A compound of formula V, VI or VII, wherein Rl is hydroqen, R2 is OR, wherein R is R6-C(O)-, or R7R8NC(o)-;
RS is hydrogen or R6-C(O)-;
R6 is alkyl havinq from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms, can be hydrolyzed to yield the respective corresponding compound of formula V, VI or VII wherein Rl is hydrogen, R2 is hydroxy and R5 is hydrogen. The hydrolysis can be carried out in an aqueous alkaline medium, if desired also containing an alcohol (e.g., methanol). Preferably the hydrolysis is carried out with NaOH (preferably 0.5 NaOH) under reflux of the aqueous alcohol-free medium.
(i) A compound of formula V or VI wherein Rl is hydrogen and R2 is hydroxy is dehydrated to form the corresponding respective compound of formula V or VI
~256~05 wherein Rl and R2 together form a bond. The reaction can be carried out with dicyclohexylcarbodiimide (DCC) in the presence of a catalyst such as, for example, CuCl in an organic solvent such as an ether, preferably diethylether.
The above processes are followed by isolation of the individual compounds and/or formation of salts and/or solvates. The compounds in their enantiomeric form can be isolated from the racemic mixture according to known methods.
Compounds of formula VIII may be prepared by methods known in the art. See, for example, U.S. Patent 4,492,702. An example of such a procedure is provided in Preparation 1.
Representative of the compounds of this invention of formulae V, VI and VII are the following:
3,5-dihydro-2-(hydroxymethyl)-5-phenyl-furo(3,2-c)-1,8-naphthyridin-4~2H)-one, 5-(3-chlorophenyl)-3,5-dihydro-2-(hydroxymethyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one,
2-(acetyloxymethyl)-3,5-dihydro-5-phenyl-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(acetyloxymethyl)-3,5-dihydro-5-~3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one,
3,5-dihydro-2-(iodomethyl)-5-phenyl-furot3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodomethyl)-5-(3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, Z56~05 3,5-dihydro-S-phenyl-2-(1-pyrrolidinylmethyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one~
3,5-dihydro-5-phenyl-2-(1-piperidinylmethyl)-furo(3,2-c)-1,8-naphthyridin-4-(2H~-one, 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-9-phenyl-2-(1-pyrrolidinylmethyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-methoxyphenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-(iodomethyl)-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-methylene-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3-hydroxy-6-phenyl-2,3,4,6-tetrahydro-SH-pyrano(3,2-c)-1,8-naphthyridin-S-one, 3-acetyloxy-6-phenyl-2,3,4,6-tetrahydro-SH-pyrano(3,2-c)-1,8-naphthyridin-5-one, 2-(hydroxymethyl)-3,5-dihydro-S-(3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-chlorophenyl)-furo(2,3-b)-1,8-naphthyridin-4~2H)-one, (in the form of the racemic mixtures or the enantiomers) or ~ i.
1.2561C115 pharmaceutically ~cceptable sal~s or solvate~
thereof.
The compounds of this invention can be used to treat allergy caused diseases and their preferred use is for treating allergic chronic obstructive lung diseases. Chronic obstructive lung disease as used herein means disease conditions in which the passage of air through the lungs is obstructed or diminished such as is the case in asthma, bronchitis and the like.
The anti-allergy method of this invention is identified by tests which measure a compound's inhihition of anaphylactic bronchospasm in sensitized rats having antigen induced bronchoconstriction. For example, the compound 3,5-dihydro-2-(hydroxymethyl)-5-phenyl-furo-~3,2-c]-1,8-naphthyridin-4(2H)-one was found to inhibit anaphylactic bronchospasm in such a test procedure when given at an oral dose of 2 mg/kg. Said compound was also found to inhibit allergen-induced histamine release from guinea pig sensitized tissue. The compounds are effec-tive non-adrenergic, non-anticholinergic antianaphylactic agents. When administered orally they are active at doses from about 0.1 to 10 mg/kg of body weight; when administered parenterally, e.g., intravenously, the compounds are active at dosages of from about 0.05 to 5 mg/kg body weight; when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.25 to 5 mg per puff, and one to four puffs may be taken every 4 hours.
The compounds of this invention are also useful for the treatment of inflammation. The anti-inflammatory use of the compounds of the present invention may be demonstrated by the Reversed Passive Arthus Reaction (RPAR) Rat Paw technique as set forth below. The potency of the compounds is determined using indomethacin as the standard. On the basis of the test results, an oral ~256~L05 dosage range of about 5 milligram~ per kilogram of body weight per day to about 50 milligrams per kilogram of body weight per day in divided doses taken at about 4 hour intervals is recommended.
The dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the inflammatory condition. Thus, the dose ultimately decided upon must be left to the judgment o~ a trained health-care practitioner.
~PAR Rat Paw Technique Animals, Materials and Methods Male Lewis inbred albino rats weighing 180-200 grams obtained from Charles River Breeding Laboratories are used in these experiments. The rats are housed 3 animals/cage and food and water are allowed ad libitum.
The animals are numbered 1-3 in each cage and color marked for identification purposes.
Drug and Reagent Preparation All reagents and drugs are prepared just prior to the study. Crystallized and lyophilized bovine serum albumin (BSA), obtained from Sigma Chemical Company, is solubilized without shaking in cold sterile pyrogen free saline (10 mg/ml). Lyophilized anti-bovine serum albumin (IGG fraction), obtained from Cappel Laboratories, is suspended in sterile distilled water and diluted with cold pyrogen free saline (PFS) just prior to use. The final concentration of anti-bovine serum albumin is 0.5 mg/ml of PFS. Both BSA and anti-BSA solutions are iced during use. Drugs are suspended or solubilized in an aqueous solution of methyl cellulose (MC) with a homogenizer just prior to administration.
~56~05 Drug Administration and Induction of Inflammation Groups of animals (6/group) are dosed with drug in MC by gavage once daily for 3 days. The last dose is administered one hour prior to sensitization with 8SA.
Controls are given MC alone and a drug-standard is usually included in each assay for verification purposes. Drugs are prepared so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for the experiment. Thus each rat receives an oral dose in a volume of approximately 2.0 cc. One hour after the last dose the animals are liyhtly anesthetized with ether and "sensitized" by injection into the penile vein with 0.2 ml of PFS containing 1.0 mg of 8SA. One hour later, the animals are "challenged" in the right rear paw with subplantar injections of 0.2 ml of PFS containing 0.1 mg of anti-BSA. Immediately after the subplantar injection, the right paw is dipped (up to the lateral maleolus) into the mercury well of a plethysmograph. The volume of mercury displaced is converted to weight and recorded.
This value is considered to be the control reading for the animal. Paw volumes are also recorded with a plethysmograph during the development of the inflammation at 2 and 4 hours post-challenae.
Results Results are expressed by the change in paw volume (~ paw volume) from the control reading for each animal to that recorded 2 and 4 hours post-challenge.
All drug treated groups are compared to the MC control for significant differences with an analysis of variance. Differences from control in drug-treated groups are expressed as percent change from control.
~256~0S
When administered parenterally, e.g. intra-venously, the compounds are administered at a dosage range of about 0.01-10 mg/kg of body weight in single or multiple daily doses.
As mentioned ahove, the subject compounds possess anti-allerqy and anti-inflammatory activities.
For example, the compound 3,5-dihydro-2-hydroxymethyl-s-phenyl-furo(3~2-c)-l~8-naphthyridin ~4(2H)-one (compound A)has an ED50 value of below about 2 mg/k~ p.o. in tests measuring the inhihition of anaphylactic bronchospasm in sensitized guinea pigs having antigen-induced bronchoconstriction and an ED50 value of below about 25 mg/k~ p.o. in tests measuring the reverse passive Arthus reaction in the paw of rats (as described above).
~256105 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharma-ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disinteqrating agents; it can also be an encapsulating material. In powders, the carrier is a fineiy divided soiid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary hinding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or lO to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "pre-paration" is intended to include the formulation of the active compound with encapsulating material as carrier ~25610S
providing a capsule in which the active component (with or without othsr carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax such as a mixture of ~atty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternately, sufficient solid may be pro-~ 256~0~;
vided so that after conversion to liquid form, multipleindividual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container.
When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The solvent utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. ~aturally, the solvent utilized will be chosen with regard to the route of administra-tion, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packete~
tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other therapeutic agents.
~2S6~05 The dosages may be varied depending upon the requirements of the patient, the severity of the con-dition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art.
Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
.~
:`:
1256~05 PREPARATION AND EXA~PLES
3,5-dihydro-5-phenyl-2-(1-piperidinylmethyl)-furo(3,2-c)-1,8-naphthyridin-4-(2H~-one, 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-9-phenyl-2-(1-pyrrolidinylmethyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-methoxyphenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-(iodomethyl)-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-methylene-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3-hydroxy-6-phenyl-2,3,4,6-tetrahydro-SH-pyrano(3,2-c)-1,8-naphthyridin-S-one, 3-acetyloxy-6-phenyl-2,3,4,6-tetrahydro-SH-pyrano(3,2-c)-1,8-naphthyridin-5-one, 2-(hydroxymethyl)-3,5-dihydro-S-(3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-chlorophenyl)-furo(2,3-b)-1,8-naphthyridin-4~2H)-one, (in the form of the racemic mixtures or the enantiomers) or ~ i.
1.2561C115 pharmaceutically ~cceptable sal~s or solvate~
thereof.
The compounds of this invention can be used to treat allergy caused diseases and their preferred use is for treating allergic chronic obstructive lung diseases. Chronic obstructive lung disease as used herein means disease conditions in which the passage of air through the lungs is obstructed or diminished such as is the case in asthma, bronchitis and the like.
The anti-allergy method of this invention is identified by tests which measure a compound's inhihition of anaphylactic bronchospasm in sensitized rats having antigen induced bronchoconstriction. For example, the compound 3,5-dihydro-2-(hydroxymethyl)-5-phenyl-furo-~3,2-c]-1,8-naphthyridin-4(2H)-one was found to inhibit anaphylactic bronchospasm in such a test procedure when given at an oral dose of 2 mg/kg. Said compound was also found to inhibit allergen-induced histamine release from guinea pig sensitized tissue. The compounds are effec-tive non-adrenergic, non-anticholinergic antianaphylactic agents. When administered orally they are active at doses from about 0.1 to 10 mg/kg of body weight; when administered parenterally, e.g., intravenously, the compounds are active at dosages of from about 0.05 to 5 mg/kg body weight; when administered by inhalation (aerosol or nebulizer) the compounds are active at dosages of about 0.25 to 5 mg per puff, and one to four puffs may be taken every 4 hours.
The compounds of this invention are also useful for the treatment of inflammation. The anti-inflammatory use of the compounds of the present invention may be demonstrated by the Reversed Passive Arthus Reaction (RPAR) Rat Paw technique as set forth below. The potency of the compounds is determined using indomethacin as the standard. On the basis of the test results, an oral ~256~L05 dosage range of about 5 milligram~ per kilogram of body weight per day to about 50 milligrams per kilogram of body weight per day in divided doses taken at about 4 hour intervals is recommended.
The dosage to be administered and the route of administration depends upon the particular compound used, the age and general health of the patient and the severity of the inflammatory condition. Thus, the dose ultimately decided upon must be left to the judgment o~ a trained health-care practitioner.
~PAR Rat Paw Technique Animals, Materials and Methods Male Lewis inbred albino rats weighing 180-200 grams obtained from Charles River Breeding Laboratories are used in these experiments. The rats are housed 3 animals/cage and food and water are allowed ad libitum.
The animals are numbered 1-3 in each cage and color marked for identification purposes.
Drug and Reagent Preparation All reagents and drugs are prepared just prior to the study. Crystallized and lyophilized bovine serum albumin (BSA), obtained from Sigma Chemical Company, is solubilized without shaking in cold sterile pyrogen free saline (10 mg/ml). Lyophilized anti-bovine serum albumin (IGG fraction), obtained from Cappel Laboratories, is suspended in sterile distilled water and diluted with cold pyrogen free saline (PFS) just prior to use. The final concentration of anti-bovine serum albumin is 0.5 mg/ml of PFS. Both BSA and anti-BSA solutions are iced during use. Drugs are suspended or solubilized in an aqueous solution of methyl cellulose (MC) with a homogenizer just prior to administration.
~56~05 Drug Administration and Induction of Inflammation Groups of animals (6/group) are dosed with drug in MC by gavage once daily for 3 days. The last dose is administered one hour prior to sensitization with 8SA.
Controls are given MC alone and a drug-standard is usually included in each assay for verification purposes. Drugs are prepared so as to provide a dose for a 200 gram animal which is equivalent to the mg/kg dose for the experiment. Thus each rat receives an oral dose in a volume of approximately 2.0 cc. One hour after the last dose the animals are liyhtly anesthetized with ether and "sensitized" by injection into the penile vein with 0.2 ml of PFS containing 1.0 mg of 8SA. One hour later, the animals are "challenged" in the right rear paw with subplantar injections of 0.2 ml of PFS containing 0.1 mg of anti-BSA. Immediately after the subplantar injection, the right paw is dipped (up to the lateral maleolus) into the mercury well of a plethysmograph. The volume of mercury displaced is converted to weight and recorded.
This value is considered to be the control reading for the animal. Paw volumes are also recorded with a plethysmograph during the development of the inflammation at 2 and 4 hours post-challenae.
Results Results are expressed by the change in paw volume (~ paw volume) from the control reading for each animal to that recorded 2 and 4 hours post-challenge.
All drug treated groups are compared to the MC control for significant differences with an analysis of variance. Differences from control in drug-treated groups are expressed as percent change from control.
~256~0S
When administered parenterally, e.g. intra-venously, the compounds are administered at a dosage range of about 0.01-10 mg/kg of body weight in single or multiple daily doses.
As mentioned ahove, the subject compounds possess anti-allerqy and anti-inflammatory activities.
For example, the compound 3,5-dihydro-2-hydroxymethyl-s-phenyl-furo(3~2-c)-l~8-naphthyridin ~4(2H)-one (compound A)has an ED50 value of below about 2 mg/k~ p.o. in tests measuring the inhihition of anaphylactic bronchospasm in sensitized guinea pigs having antigen-induced bronchoconstriction and an ED50 value of below about 25 mg/k~ p.o. in tests measuring the reverse passive Arthus reaction in the paw of rats (as described above).
~256105 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharma-ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disinteqrating agents; it can also be an encapsulating material. In powders, the carrier is a fineiy divided soiid which is in admixture with the finely divided active compound. In the tablet the active compound is mixed with carrier having the necessary hinding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 or lO to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "pre-paration" is intended to include the formulation of the active compound with encapsulating material as carrier ~25610S
providing a capsule in which the active component (with or without othsr carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax such as a mixture of ~atty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternately, sufficient solid may be pro-~ 256~0~;
vided so that after conversion to liquid form, multipleindividual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon or other volumetric container.
When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition. The solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The solvent utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol and the like as well as mixtures thereof. ~aturally, the solvent utilized will be chosen with regard to the route of administra-tion, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packete~
tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself or it can be the appropriate number of any of these in packaged form.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other therapeutic agents.
~2S6~05 The dosages may be varied depending upon the requirements of the patient, the severity of the con-dition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art.
Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
.~
:`:
1256~05 PREPARATION AND EXA~PLES
4-HYDROXY-l-PHENYL-3-(2-PROPENYL)-1,8-NAPHTHYRIDIN-2(lH)-ONE
(A) 4-HYdroxY-l-phenyl-1,8-naPhthvridin-2(lH)-one To a stirred solution of 1 kg. of methyl 2-phenylamino-3-pyridine carboxylate in 3.97 liters of n-butyl acetate there is added portionwise, 1.1 kg. of potassium tertiary butoxide. After the addition of the potassium tertiary butoxide, there is added an additional 1.32 liters of n-butyl acetate. The reaction mixture is heated to reflux for 20 hours during which the internal temperature of the reaction mixture rises from 30C to 122C. During this period, 1.8 liters of liquid is removed from the reaction via a Dean-Stark trap. Xylene (3.0 liters) is added to the reaction mixture and the remainder of the n-butyl acetate is removed via the Dean-Stark trap. The reaction mixture is cooled and the potassium salt is collected by filtration, washed with toluene and air dried. The crude potassium salt is dissolved in 12 liters of water, the aqueous solution is extracted with toluene, acidified to pH 2 and the product filtered and dried: weight 937 9., m.p. 311-313C.
(B) 4-Acetvloxv-l-phenvl-3-(2-propenvl)-1,8-naphthyridin-2(lH)-one 1.) 1-phenvl-4-(2-Propenyloxy)-1,8-naphthYridin-2(lH)-one:
To a mixture of 62 9. of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(lH)-one, 39.6 9. of anhydrous potassium carbonate and 1,800 ml of acetone, there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 : ::
~ ml. of chloroform. The organic extract is washed with ~ ~25610S
water, lN sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3 x 400 ml of boiling isopropyl ether and filtered, yielding the insoluble product, wt. 38.5 g., m.p. 171-174.
Recrystallization from methanol produces the product as a colorless solid, m.p. 176-177C.
2.) 4-AcetYloxy-l-phenyl-3-(2-propenyl)-1,8-naphthyridin-2~lH)-one:
A mixture of 33.8 g. of 1-phenyl-4-(2-propenyloxy)-1,8-naphthyridin-2(lH)-one and 35 ml. of acetic anhydride is refluxed for four hours. On cooling, the reaction mixture solidified. Trituration with isopropyl ether and filtration yields the product, 36.1 g., as a colorless solid, m.p. 189-195C. Recrystalli-zation from ethanol provides the product with m.p. 195-196C.
(C) 4-Hydroxy-l-phenyl-3-(2-propenvl)-1,8-naphthyridin-2(lH)-one A mixture of 6 . O g. of 4-acetyloxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(lH)-one, 200 ml. of ethanol and 40 ml. of lN sodium hydroxide solution is stirred at room temperature for 22 hours. The ethanol is removed in vacuo and the remaining aqueous solution acidified with lN hydrochloric acid. The product is filtered, washed with water and dried, weight 5.3 q., m.p. 248-250C. Recrystallization from chloroform yields the product of this preparation as a colorless solid, m.p. 250-252C.
In a similar manner, substitute 4-bromo-1-butene for allyl bromide in part B(l) of Preparation 1 to prepare 3-(3-butenyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(lH)-one.
.. .
~,2S6io~
2-(BROMOMETHYL)-3,9-DIHYDRO-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To a cooled (5) solution of 24.5 g. (0.076 moles) of 4-(acetyloxy)-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(lH)-one in 350 ml. of dry chloroform there is added dropwise, 12.2 g. (0.076 moles) of bromine. The reaction mixture is allowed to come to room temperature, stirred for 18 hours, concentrated in vacuo, and the solid product is triturated with 3 x 150 ml. of isopropyl ether and filtered. The crude hydrobromide salt melts at 20g-211(dec), and on recrystallization from ethanol melts at 212-213(dec).
The hydrobromide salt is readily treated with cold 0.1 N sodium hydroxide solution, then recrystallized from ethyl acetate to yield the title compound, m.p. 187-188C.
3,5-DIHYDRO-2-~HYDROXYMETHYL)-5-PHENYL-FURO(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
A solution of 15.0 g. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one hydrobromide in 200 ml of methanol, 160 ml of 1.0 N
sodium hydroxide solution and 150 ml. of water is stirred and refluxed on a steam bath for 21 hours. The reaction is concentrated to a volume of 200 ml in vacuo and the solid filtered and washed with water. Recrystallization of the crude solid from methanol yields the title compound, m.p. 267-268.
2-(ACETYLOXYMETHYL)-3,5-DIHYDRO-5-PHENYL-F~RO(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
The product of Example 2 is refluxed with acetic anhydride in benzene, and the resultant product is ~Z5610S
recry~tallized from isopropyl acetate to give the title compound, m.p. 207-208C.
3-ACETYLOXY-2,3,4 6-TETRAHYDRo-6-PHENYL-5H-PYRANo~3,2-c)-1,8-NAPHTHYRIDIN-5-ONE
A solution of 51.0 9. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 680 ml. of methanol, 545 ml. of 1.0 N sodium hydroxide solution and 510 ml. of water is stirred and refluxed on a steam bath for 18 hours. The solution is concentrated in vacuo to a volume of 600 ml., cooled, and the solids filtered and washed with water. Spectral data and chromato~raphy indicated the presence of two compounds, the product of Example 2 ("compound 2n) and the title compound of example 5. After separation of most of "compound 2R the mother liquor is acetylated with acetic anhydride in refluxin~ benzene, yielding a mixture of the acetates which are separated by chromatography, yielding the title compound, m.p. 224-226C.
3-HYDRoXY-2~3,4,6-TETRAHYDRO-6-PHENYL-5H-PYRANO(3,2-c)-1,8-NAPHTHYRIDIN-5-ONE
Hydrolysis of the product of Example 4 with methanol:l.0 N sodium hydroxide solution followed by recrystallization of the resultant product from methanol yields the title compound, m.p. 296-298C.
2-(BROMOMETHYL)-3,9-DIHYDRO-9-t3-METHOXYPHENYL)-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4~2H)-ONE
Treat 4-hydroxy-1-(3-methoxyphenyl)-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one according to the procedure described in Example 1, recrystallizing from .~
25610~
methanol:ethyl acetate to obtain the title compound, m.p.
196-198C.
EXAMPLE ?
2-(ACETYLOXYMETHYL)-3,5-DIHYDRO-5-(3-METHOXYPHENYL)-FURO-(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
-Treat 2-(bromomethyl)-3,9-dihydro-9-(3-methoxyphenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one according to the procedure of Example 2 to prepare the 2-hydroxymethyl analog of the title compound. Trea~ this 2-hydroxymethyl compound according to the procedures of Example 3 to obtain the title compound, m.p. 183-184C.
3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To a solution of 4.0 9. (0.014 moles) of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(lH)-one in 380 ml. of tetrahydrofuran, there is added, dropwise, with stirring at 3-5C, 4.09. of 70% perchloric acid in 11.5 ml. of water, followed by the slow addition of 10.29. of N-iodo-succinimide over a period of 45 minutes. The reaction is stirred at room temperature for three hours, treated with a saturated solution of sodium sulfite, and extracted with 2 x 250 ml. of ether. The organic layer is dried over magnesium sulfate, filtered and concentrated to a solid residue. The crude products are separated on a 60G silica gel column with methanol:
chloroform (5:95). The desired fraction is recrystalli~ed from ethyl acetate to yield the title compound, m.p. 178-180C.
~25~105 3,5-DIHYDRO-2~IODOMETHYL)-5-PHENYL-FURO(3,2-c)-1,8-NAPHTHYRIDIN-4~2H)-ONE
The desired fraction comprising the compound of this example isolated from the column chromatography carried out in Example 8 is recrystallized from acetonitrile to yield the title compound, m.p. 238-240C.
3,9-DIHYDRO-2-METHYLENE-9-PHENYL-FUROt2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
A solution of 2 g. of 3,9-dihydro-2-(iodo-methyl)-9-phenyl-furo~2,3-b)-1,8-naphthyridin-4~2H)-one in 4 ~. of dry piperidine is stirred at room temperature for 72 hours. The reaction mixture is diluted with 80 ml. of water, filtered and the solids washed well with wat~r, The aqueous filtrate is made strongly basic with sodium hydroxide solution and filtered. The combined solids are purified on a grade 62 silica gel column using
(A) 4-HYdroxY-l-phenyl-1,8-naPhthvridin-2(lH)-one To a stirred solution of 1 kg. of methyl 2-phenylamino-3-pyridine carboxylate in 3.97 liters of n-butyl acetate there is added portionwise, 1.1 kg. of potassium tertiary butoxide. After the addition of the potassium tertiary butoxide, there is added an additional 1.32 liters of n-butyl acetate. The reaction mixture is heated to reflux for 20 hours during which the internal temperature of the reaction mixture rises from 30C to 122C. During this period, 1.8 liters of liquid is removed from the reaction via a Dean-Stark trap. Xylene (3.0 liters) is added to the reaction mixture and the remainder of the n-butyl acetate is removed via the Dean-Stark trap. The reaction mixture is cooled and the potassium salt is collected by filtration, washed with toluene and air dried. The crude potassium salt is dissolved in 12 liters of water, the aqueous solution is extracted with toluene, acidified to pH 2 and the product filtered and dried: weight 937 9., m.p. 311-313C.
(B) 4-Acetvloxv-l-phenvl-3-(2-propenvl)-1,8-naphthyridin-2(lH)-one 1.) 1-phenvl-4-(2-Propenyloxy)-1,8-naphthYridin-2(lH)-one:
To a mixture of 62 9. of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(lH)-one, 39.6 9. of anhydrous potassium carbonate and 1,800 ml of acetone, there is added dropwise, with stirring, 37.5 g. of allyl bromide. The reaction mixture is refluxed for 22 hours, concentrated in vacuo, and the residue extracted with 600 : ::
~ ml. of chloroform. The organic extract is washed with ~ ~25610S
water, lN sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is triturated with 3 x 400 ml of boiling isopropyl ether and filtered, yielding the insoluble product, wt. 38.5 g., m.p. 171-174.
Recrystallization from methanol produces the product as a colorless solid, m.p. 176-177C.
2.) 4-AcetYloxy-l-phenyl-3-(2-propenyl)-1,8-naphthyridin-2~lH)-one:
A mixture of 33.8 g. of 1-phenyl-4-(2-propenyloxy)-1,8-naphthyridin-2(lH)-one and 35 ml. of acetic anhydride is refluxed for four hours. On cooling, the reaction mixture solidified. Trituration with isopropyl ether and filtration yields the product, 36.1 g., as a colorless solid, m.p. 189-195C. Recrystalli-zation from ethanol provides the product with m.p. 195-196C.
(C) 4-Hydroxy-l-phenyl-3-(2-propenvl)-1,8-naphthyridin-2(lH)-one A mixture of 6 . O g. of 4-acetyloxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(lH)-one, 200 ml. of ethanol and 40 ml. of lN sodium hydroxide solution is stirred at room temperature for 22 hours. The ethanol is removed in vacuo and the remaining aqueous solution acidified with lN hydrochloric acid. The product is filtered, washed with water and dried, weight 5.3 q., m.p. 248-250C. Recrystallization from chloroform yields the product of this preparation as a colorless solid, m.p. 250-252C.
In a similar manner, substitute 4-bromo-1-butene for allyl bromide in part B(l) of Preparation 1 to prepare 3-(3-butenyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(lH)-one.
.. .
~,2S6io~
2-(BROMOMETHYL)-3,9-DIHYDRO-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To a cooled (5) solution of 24.5 g. (0.076 moles) of 4-(acetyloxy)-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(lH)-one in 350 ml. of dry chloroform there is added dropwise, 12.2 g. (0.076 moles) of bromine. The reaction mixture is allowed to come to room temperature, stirred for 18 hours, concentrated in vacuo, and the solid product is triturated with 3 x 150 ml. of isopropyl ether and filtered. The crude hydrobromide salt melts at 20g-211(dec), and on recrystallization from ethanol melts at 212-213(dec).
The hydrobromide salt is readily treated with cold 0.1 N sodium hydroxide solution, then recrystallized from ethyl acetate to yield the title compound, m.p. 187-188C.
3,5-DIHYDRO-2-~HYDROXYMETHYL)-5-PHENYL-FURO(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
A solution of 15.0 g. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one hydrobromide in 200 ml of methanol, 160 ml of 1.0 N
sodium hydroxide solution and 150 ml. of water is stirred and refluxed on a steam bath for 21 hours. The reaction is concentrated to a volume of 200 ml in vacuo and the solid filtered and washed with water. Recrystallization of the crude solid from methanol yields the title compound, m.p. 267-268.
2-(ACETYLOXYMETHYL)-3,5-DIHYDRO-5-PHENYL-F~RO(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
The product of Example 2 is refluxed with acetic anhydride in benzene, and the resultant product is ~Z5610S
recry~tallized from isopropyl acetate to give the title compound, m.p. 207-208C.
3-ACETYLOXY-2,3,4 6-TETRAHYDRo-6-PHENYL-5H-PYRANo~3,2-c)-1,8-NAPHTHYRIDIN-5-ONE
A solution of 51.0 9. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 680 ml. of methanol, 545 ml. of 1.0 N sodium hydroxide solution and 510 ml. of water is stirred and refluxed on a steam bath for 18 hours. The solution is concentrated in vacuo to a volume of 600 ml., cooled, and the solids filtered and washed with water. Spectral data and chromato~raphy indicated the presence of two compounds, the product of Example 2 ("compound 2n) and the title compound of example 5. After separation of most of "compound 2R the mother liquor is acetylated with acetic anhydride in refluxin~ benzene, yielding a mixture of the acetates which are separated by chromatography, yielding the title compound, m.p. 224-226C.
3-HYDRoXY-2~3,4,6-TETRAHYDRO-6-PHENYL-5H-PYRANO(3,2-c)-1,8-NAPHTHYRIDIN-5-ONE
Hydrolysis of the product of Example 4 with methanol:l.0 N sodium hydroxide solution followed by recrystallization of the resultant product from methanol yields the title compound, m.p. 296-298C.
2-(BROMOMETHYL)-3,9-DIHYDRO-9-t3-METHOXYPHENYL)-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4~2H)-ONE
Treat 4-hydroxy-1-(3-methoxyphenyl)-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one according to the procedure described in Example 1, recrystallizing from .~
25610~
methanol:ethyl acetate to obtain the title compound, m.p.
196-198C.
EXAMPLE ?
2-(ACETYLOXYMETHYL)-3,5-DIHYDRO-5-(3-METHOXYPHENYL)-FURO-(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
-Treat 2-(bromomethyl)-3,9-dihydro-9-(3-methoxyphenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one according to the procedure of Example 2 to prepare the 2-hydroxymethyl analog of the title compound. Trea~ this 2-hydroxymethyl compound according to the procedures of Example 3 to obtain the title compound, m.p. 183-184C.
3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To a solution of 4.0 9. (0.014 moles) of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(lH)-one in 380 ml. of tetrahydrofuran, there is added, dropwise, with stirring at 3-5C, 4.09. of 70% perchloric acid in 11.5 ml. of water, followed by the slow addition of 10.29. of N-iodo-succinimide over a period of 45 minutes. The reaction is stirred at room temperature for three hours, treated with a saturated solution of sodium sulfite, and extracted with 2 x 250 ml. of ether. The organic layer is dried over magnesium sulfate, filtered and concentrated to a solid residue. The crude products are separated on a 60G silica gel column with methanol:
chloroform (5:95). The desired fraction is recrystalli~ed from ethyl acetate to yield the title compound, m.p. 178-180C.
~25~105 3,5-DIHYDRO-2~IODOMETHYL)-5-PHENYL-FURO(3,2-c)-1,8-NAPHTHYRIDIN-4~2H)-ONE
The desired fraction comprising the compound of this example isolated from the column chromatography carried out in Example 8 is recrystallized from acetonitrile to yield the title compound, m.p. 238-240C.
3,9-DIHYDRO-2-METHYLENE-9-PHENYL-FUROt2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
A solution of 2 g. of 3,9-dihydro-2-(iodo-methyl)-9-phenyl-furo~2,3-b)-1,8-naphthyridin-4~2H)-one in 4 ~. of dry piperidine is stirred at room temperature for 72 hours. The reaction mixture is diluted with 80 ml. of water, filtered and the solids washed well with wat~r, The aqueous filtrate is made strongly basic with sodium hydroxide solution and filtered. The combined solids are purified on a grade 62 silica gel column using
5 pts MeOH, 95 pts ethyl acetate as solvent. Fraction lII is triturated with 2 x 50 ml. of hot isopropyl ether yielding the title compound, m.p. 259-261C.
3,9-DIHYDRO-9-PHENYL-2-~1-PYRROLIDINYLMETHYL)-F~RO(2,3-b)-1,8-NAPHTHYRIDIN-4~2H)-ONE HYDROCHLORIDE
A mixture of 10.0 g. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one and 22g. of pyrrolidine is stirred at room temperature for three hours. The reaction mixture is diluted with 180 ml. of water, the solids washed well with water and air dried. The crude product is treated with excess 1 N
hydrochloric acid solution, extracted with methylene chloride and the aqueous acidic layer separated. The acidic layer is basified with dilute sodium hydroxide solution, cooled and filtered to yield a crude product, L256~0S
m.p. 159-160. Recry~tallization from ethyl acetate yields the title compound, m.p. 161-163; hydrochloride salt as a hydrate, m.p. 187-190C from ethanol:ether.
3,5-DIHYDR0-5-(3-CHLOROPHENYL)-2-(HYDROXYMETHYL)-FUR0(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
In a manner similar to that described in Example 2, treat 2-(bromomethyl)-9-(3-chlorophenyl)-3,9-dihydro-furo(2,3-b)-1,8-naphthyridin-4(2H)-one to yield the title compound, m.p. 243-245C.
3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To a solution of 2 mmole of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 100 ml of methylene chloride there is added a solution of 2.2 mmole of iodine monochloride. The solution is stirred at room temperature until starting material could no longer be detected (e.g. by thin layer chromatography). The methylene chloride was removed in vaccuo and the title compound recrystallized from ethyl acetate, m.p. 178-180C.
3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To 2.3 mmole of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 100 ml of methylene chloride was added 2.3 mmol of anhydrous potassium carbonate and 2.76 mmol. of iodine. The reaction mixture was stirred for 15 hours at room temperature, quenched with water and the organic layer dried and concentrated to yield the title compound (m.p.
178-180C).
3,9-DIHYDRO-9-PHENYL-2-~1-PYRROLIDINYLMETHYL)-F~RO(2,3-b)-1,8-NAPHTHYRIDIN-4~2H)-ONE HYDROCHLORIDE
A mixture of 10.0 g. of 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one and 22g. of pyrrolidine is stirred at room temperature for three hours. The reaction mixture is diluted with 180 ml. of water, the solids washed well with water and air dried. The crude product is treated with excess 1 N
hydrochloric acid solution, extracted with methylene chloride and the aqueous acidic layer separated. The acidic layer is basified with dilute sodium hydroxide solution, cooled and filtered to yield a crude product, L256~0S
m.p. 159-160. Recry~tallization from ethyl acetate yields the title compound, m.p. 161-163; hydrochloride salt as a hydrate, m.p. 187-190C from ethanol:ether.
3,5-DIHYDR0-5-(3-CHLOROPHENYL)-2-(HYDROXYMETHYL)-FUR0(3,2-c)-1,8-NAPHTHYRIDIN-4(2H)-ONE
In a manner similar to that described in Example 2, treat 2-(bromomethyl)-9-(3-chlorophenyl)-3,9-dihydro-furo(2,3-b)-1,8-naphthyridin-4(2H)-one to yield the title compound, m.p. 243-245C.
3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To a solution of 2 mmole of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 100 ml of methylene chloride there is added a solution of 2.2 mmole of iodine monochloride. The solution is stirred at room temperature until starting material could no longer be detected (e.g. by thin layer chromatography). The methylene chloride was removed in vaccuo and the title compound recrystallized from ethyl acetate, m.p. 178-180C.
3,9-DIHYDRO-2-(IODOMETHYL)-9-PHENYL-FURO(2,3-b)-1,8-NAPHTHYRIDIN-4(2H)-ONE
To 2.3 mmole of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 100 ml of methylene chloride was added 2.3 mmol of anhydrous potassium carbonate and 2.76 mmol. of iodine. The reaction mixture was stirred for 15 hours at room temperature, quenched with water and the organic layer dried and concentrated to yield the title compound (m.p.
178-180C).
Claims (14)
1) A compound of the formula I
wherein A is a moiety of the formula II, III or IV
II III IV
wherein n is 1 or 2;
R1 and R2 may be combined to form a bond, or is hydrogen and R2 is OR, halogen or NR3R4;
R is hydrogen, R6-C(O)-, or R7R8NC(O)-;
R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring;
R5 is hydrogen or R6-C(O)-;
R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms;
X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2;
p is 1, 2 or 3; and Y is CH or N;
and the acid addition salts and/or solvates thereof.
wherein A is a moiety of the formula II, III or IV
II III IV
wherein n is 1 or 2;
R1 and R2 may be combined to form a bond, or is hydrogen and R2 is OR, halogen or NR3R4;
R is hydrogen, R6-C(O)-, or R7R8NC(O)-;
R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring;
R5 is hydrogen or R6-C(O)-;
R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms;
X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, nitro, halogen, trifluoromethyl or alkyl-S(O)m having from 1 to 6 carbon atoms, and wherein m is zero, 1 or 2;
p is 1, 2 or 3; and Y is CH or N;
and the acid addition salts and/or solvates thereof.
2) A compound according to claim 1, wherein A is the moiety of formulae II or III.
3) A compound according to claim 2, wherein Y is CH and n is 1.
4) A compound according to claim 2 or claim 3, wherein R1 is hydrogen and R2 is OR, wherein R is hydrogen or R6C(O)-, wherein R6 is alkyl or R3 is NR3R4.
5) A compound according to claim 2 or claim 3, wherein R1 is hydrogen and R2 is OR, wherein R is hydrogen or R6C(O), wherein R6 is alkyl, or R2 is 1-piperidinyl or 1-pyrrolidinyl.
6) A compound according to claim 2 or claim 3, wherein R1 is hydrogen and R2 is halogen.
7) A compound according to claim 2 or claim 3, wherein R2 is bromo or iodo.
8) A compound according to claim 2 or claim 3, wherein A is the moiety of formula II.
9) A compound according to claim 2 or claim 3 wherein p is 1 and X is hydrogen, halogen or alkoxy.
10) A compound according to claim 2 or claim 3 wherein p is 1 and X is hydrogen, chloro or methoxy.
11) A compound according to claim 1 which is 3,5-dihydro-2-(hydroxymethyl)-5-phenyl-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 5-(3-chlorophenyl)-3,5-dihydro-2-(hydroxymethyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(acetyloxymethyl)-3,5-dihydro-5-phenyl-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(acetyloxymethyl)-3,5-dihydro-5-(3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodomethyl)-5-phenyl-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-2-(iodomethyl)-5-(3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-5-phenyl-2-(1-pyrrolidinylmethyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 3,5-dihydro-5-phenyl-2-(1-piperidinylmethyl)-furo(3,2-c)-1,8-naphthyridin-4-(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-9-phenyl-2-(1-pyrrolidinylmethyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-methoxyphenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-(iodomethyl)-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3,9-dihydro-2-methylene-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, 3-hydroxy-6-phenyl-2,3,4,6-tetrahydro-5H-pyrano(3,2-c)-1,8-naphthyridin-5-one, 3-acetyloxy-6-phenyl-2,3,4,6-tetrahydro-5H-pyrano(3,2-c)-1,8-naphthyridin-5-one, 2-(hydroxymethyl)-3,5-dihydro-5-(3-methoxyphenyl)-furo(3,2-c)-1,8-naphthyridin-4(2H)-one, 2-(bromomethyl)-3,9-dihydro-9-(3-chlorophenyl)-furo(2,3-b)-1,8-naphthyridin-4(2H)-one, (in the form of the racemic mixtures or the enantiomers) or pharmaceutically acceptable salt thereof.
12) Process for the preparation of a compound of the formula I or its acid addition salt and/or solvates as defined in claim 1, characterized in that a) a compound of formula VIII
VIII
or an ester thereof is subjected to halogenation and cyclization to form compounds of formulae V and VI, V VI
wherein R1 is hydrogen and R2 is halogen; or b) a compound of formula IX
IX
is cyclized to form a compound of formula V
V
wherein R1 is hydrogen and R2 is hydroxy; or c) a compound of formula V or VI wherein R1 is hydrogen and R2 is halogen is hydrolyzed to give a compound of formula V and/or VI and/or VII
VI
V VII
wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen;
or d) a compound of formula V or VI (wherein R1 is hydrogen, R2 is hydroxy) or VII (wherein R5 is hydrogen) is esterified to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is OR wherein R is R6C(O)- or R7R8NC(O)- and R5 is R6C(O)-, wherein R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl and R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms; or e) a compound of formula V or VI wherein R1 is hydrogen and R2 is halogen is reacted with an amine HNR3R4 (wherein R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring) or with a reactive derivative of said amine to form the respective corresponding compound V or VI wherein R1 is hydrogen and R2 is NR3R4; or f) a compound of formula V or VI wherein R1 is hydrogen and R2 is halo is dehydrohalogenated to form the respective corresponding compound V or VI wherein R1 and R2 together form a bond;
g) a compound of formula VI wherein R1 is hydrogen and R2 is bromo is reacted with sodium iodide to yield a compound of formula V wherein R1 is hydrogen and R2 is iodo; or h) a compound of formulae V, VI or VII, wherein R1 is hydrogen, R2 is OR, wherein R is R6-C(O)-, or R7R8NC(O)-;
R5 is hydrogen or R6-C(O)-;
R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms, is hydrolyzed to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen;
i) a compound of formulae V or VI wherein R1 is hydrogen and R2 is hydroxy is dehydrated to yield the respective corresponding compound V or VI wherein R1 and R2 together form a bond;
whereby each of the processes is followed, if desired, by isolation of the individual compound and/or formation of the salt and/or solvate of the compound(s).
VIII
or an ester thereof is subjected to halogenation and cyclization to form compounds of formulae V and VI, V VI
wherein R1 is hydrogen and R2 is halogen; or b) a compound of formula IX
IX
is cyclized to form a compound of formula V
V
wherein R1 is hydrogen and R2 is hydroxy; or c) a compound of formula V or VI wherein R1 is hydrogen and R2 is halogen is hydrolyzed to give a compound of formula V and/or VI and/or VII
VI
V VII
wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen;
or d) a compound of formula V or VI (wherein R1 is hydrogen, R2 is hydroxy) or VII (wherein R5 is hydrogen) is esterified to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is OR wherein R is R6C(O)- or R7R8NC(O)- and R5 is R6C(O)-, wherein R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl and R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms; or e) a compound of formula V or VI wherein R1 is hydrogen and R2 is halogen is reacted with an amine HNR3R4 (wherein R3 and R4 are independently hydrogen or alkyl having from 1 to 6 carbon atoms, or R3 and R4 may be combined with the nitrogen to which they are attached to form a pyrrolidino, piperidino, morpholino or piperazino ring) or with a reactive derivative of said amine to form the respective corresponding compound V or VI wherein R1 is hydrogen and R2 is NR3R4; or f) a compound of formula V or VI wherein R1 is hydrogen and R2 is halo is dehydrohalogenated to form the respective corresponding compound V or VI wherein R1 and R2 together form a bond;
g) a compound of formula VI wherein R1 is hydrogen and R2 is bromo is reacted with sodium iodide to yield a compound of formula V wherein R1 is hydrogen and R2 is iodo; or h) a compound of formulae V, VI or VII, wherein R1 is hydrogen, R2 is OR, wherein R is R6-C(O)-, or R7R8NC(O)-;
R5 is hydrogen or R6-C(O)-;
R6 is alkyl having from 1 to 9 carbon atoms, alkenyl having from 2 to 7 carbon atoms, alkynyl having from 2 to 7 carbon atoms, phenyl, substituted phenyl (wherein the substituents are as defined for X) or benzyl;
R7 and R8 are independently hydrogen, lower alkyl having from 1 to 6 carbon atoms, or hydroxyalkyl having from 1 to 6 carbon atoms, is hydrolyzed to yield the respective corresponding compound of formula V, VI or VII wherein R1 is hydrogen, R2 is hydroxy and R5 is hydrogen;
i) a compound of formulae V or VI wherein R1 is hydrogen and R2 is hydroxy is dehydrated to yield the respective corresponding compound V or VI wherein R1 and R2 together form a bond;
whereby each of the processes is followed, if desired, by isolation of the individual compound and/or formation of the salt and/or solvate of the compound(s).
13) A process as claimed in claim 12, process e), wherein R2 is bromo.
14) A pharmaceutical composition which comprises a compound of any one of claims 1 to 3 in combination with a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US06/716,003 US4596809A (en) | 1985-03-25 | 1985-03-25 | Substituted 1,8-naphthyridinones, useful as anti-allergic agents |
US716,003 | 1985-03-25 |
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Publication Number | Publication Date |
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CA1256105A true CA1256105A (en) | 1989-06-20 |
Family
ID=24876323
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CA000504729A Expired CA1256105A (en) | 1985-03-25 | 1986-03-21 | Substituted 1,8-naphthyridinones, processes for their preparation and pharmaceutical compositions containing them |
Country Status (5)
Country | Link |
---|---|
US (1) | US4596809A (en) |
JP (1) | JPS61246183A (en) |
CA (1) | CA1256105A (en) |
PH (1) | PH21229A (en) |
ZA (1) | ZA862141B (en) |
Families Citing this family (14)
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US4687774A (en) * | 1986-03-10 | 1987-08-18 | Schering Corporation | Method for suppressing the immune response |
US4988705A (en) * | 1985-06-13 | 1991-01-29 | Schering Corporation | Polycyclic quinoline, naphthyridine and pyrazinopyridine derivatives |
US5116840A (en) * | 1985-06-13 | 1992-05-26 | Schering Corporation | Polycyclic quinoline, naphthyridine and pyrazinopyridine derivatives |
US4810708A (en) * | 1986-05-15 | 1989-03-07 | Schering Corporation | Polycyclic quinoline, naphthyridine and pyrazinopyridine derivatives |
ES2054665T3 (en) * | 1986-04-11 | 1994-08-16 | Schering Corp | NAFTIRIDINE AND PIRIDOPYRAZINE DERIVATIVES REPLACED WITH ARYL. |
US4882332A (en) * | 1986-10-20 | 1989-11-21 | Schering Corporation | Immune suppression method employing arly-substituted naphthyridine and pyridopyrazine derivatives |
US5011860A (en) * | 1986-04-11 | 1991-04-30 | Schering Corporation | Aryl-substituted naphthyridine and pyridopyrazine derivatives and their use in treating hyperproliferative skin diseases |
US4760073A (en) * | 1986-04-11 | 1988-07-26 | Schering Corporation | Aryl-substituted naphthyridine and pyridopyrazine derivatives, useful as anti-allergic agents |
US5045542A (en) * | 1986-10-20 | 1991-09-03 | Schering Corporation | Immune suppression method employing aryl-substituted naphthyridine and pyridopyrazine derivatives |
AU612437B2 (en) * | 1987-12-14 | 1991-07-11 | Kyowa Hakko Kogyo Co. Ltd. | Tricyclic compounds |
JPH089616B2 (en) * | 1990-10-10 | 1996-01-31 | シェリング・コーポレーション | Substituted imidazobenzazepines and imidazopyridazepines |
US5760034A (en) * | 1990-11-30 | 1998-06-02 | Schering Corporation | Heterocyclic substituted naphthyridinones and methods and compositions employing them |
CN101268073B (en) | 2005-09-15 | 2011-10-19 | Aska制药株式会社 | Heterocyclic compound, and production process and use thereof |
US9938268B2 (en) * | 2008-12-17 | 2018-04-10 | Merck Patent Gmbh | C-ring modified tricyclic benzonaphthiridinone protein kinase inhibitors and use thereof |
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US4680298A (en) * | 1983-05-31 | 1987-07-14 | Schering Corporation | Tricyclic anti-allergy and use as anti-inflammatory agents |
-
1985
- 1985-03-25 US US06/716,003 patent/US4596809A/en not_active Expired - Lifetime
-
1986
- 1986-03-21 ZA ZA862141A patent/ZA862141B/en unknown
- 1986-03-21 CA CA000504729A patent/CA1256105A/en not_active Expired
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JPS61246183A (en) | 1986-11-01 |
PH21229A (en) | 1987-08-21 |
US4596809A (en) | 1986-06-24 |
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